In this proposal, we will explore a novel system of innate host defense in the cardiovascular and pulmonary systems. We and others have previously demonstrated a role for the complement anaphylatoxins C5a and C3a in the host defense in the lung. We now have identified a novel 7-transmembrane receptor that is a second C5a receptor. The mRNA for this receptor, besides being present on granulocytes, is most abundant in the heart and lung. While binding C5a with high affinity, the receptor in mouse and man bears a mutation in the region of the protein essential for coupling to G proteins. We will explore the hypothesis that this second C5a receptor mediates novel signaling properties independent of G proteins, and may serve as a regulator of the pro-inflammatory characterized C5a receptor. The characterization of this second C5a receptor may elucidate novel pathways for regulation of host defense and inflammation in the lung. Further, completion of these aims will allow further insight into mechanisms by which rational therapies for inflammatory lung disease may be approached.